The tobacco-specific carcinogen NNK induces pulmonary tumorigenesis via nAChR/Src/STAT3-mediated activation of the renin-angiotensin system and IGF-1R signaling.

ABSTRACT: The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the representative tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes lung tumorigenesis through deregulation of the pulmonary RA system. Mechanistically, NNK binding to the nicotinic acetylcholine receptor (nAChR) induces Src-mediated signal transducer and activator of transcription 3 (STAT3) activation, resulting in transcriptional upregulation of angiotensinogen (AGT) and subsequent induction of the angiotensin II (AngII) receptor type 1 (AGTR1) signaling pathway. In parallel, NNK concurrently increases insulin-like growth factor 2 (IGF2) production and activation of IGF-1R/insulin r

SUBMITTER: Boo HJ 

PROVIDER: S-EPMC10317988 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature